Glaucoma is the second most common cause of blindness in the world. Our project seeks to specify new approaches to its therapy by extending the lives of retinal ganglion cells through treatments that would supplement eye pressure lowering therapy that is now the standard of care. These experiments will elucidate the mechanism of blindness in glaucoma through use of experimental models in rats and monkeys and through study of human eyes with glaucoma. The role of neurotrophins in the maintenance of normal retinal ganglion cell health will be investigated. The hypothesis will be examined that neurotrophin deprivation is an important factor in ganglion cell death in glaucoma by interfering with normal signaling between target brain cells and retinal ganglion cells. The project will investigate the role of microtubule associated proteins within ganglion cell fibers in the obstruction of axonal transport known to occur in glaucoma. It includes expression of genes for neurotrophins, especially brain-deprived neurotrophic factor, in ganglion cells using viral vectors to assess the beneficial effect on chronic experimental glaucoma. Another aim is to determine whether cysteine proteases are activated during the death of ganglion cells in glaucoma. If these enzymes are found to be involved, their inhibition will be studied by ganglion cell expression of genes that inhibit them, again using viral vectors. A transgenic rat model will be developed that expresses an inhibitory protein for apoptotic cells death (p35) under conditional control of expression by exposure to tetracycline. In these rats, induced neuronal expression will be studied in a chronic glaucoma model to assess beneficial effects.